DESCRIPTION: The long-term objective of this proposal is to study the pathogenesis of ocular cicatricial pemphigoid (OCP). About 25 percent of OCP patients can become blind and generalized cicatricial pemphigoid (CP) is potentially fatal. The hypothesis is that the antigen(s) to which antibasement membrane zone (BMZ) antibodies are produced in OCP are adhesion molecules that bind the basal conjunctival cell to extracellular matrix and the basement membrane (BM). The main specific aim of this grant proposal is to characterize this molecule(s) using biochemical, immunochemical, cellular and molecular techniques. Recent publications and preliminary results indicate that in the group of OCP patients studied, their sera recognize human 4 integrin as the target antigen. In the proposed studies they plan to investigate the role of human 4 in hemidesmosome assembly in conjunction with BPAg1 and BPAg2. In the experiments they will investigate the mechanism by which anti-B4 antibody (OCP sera) disassemble the hemidesmosome and the result in the separation of basal conjunctival cells from the underlying basement membrane and study some of the signals that mediate these processes. A human conjunctiva organ culture explant in vitro model for OCP will be developed. This model will help determine whether the process of blister formation requires only a single step of hemidesmosomal dissolution by autoantibody or is a complex process involving a cascade of multiple events. If it is a multistep process, this model will allow the analyses of the sequential biochemical and molecular events that lead to subepithelial blister formation in OCP. It will also prove an opportunity to test the ability of various pharmacological and therapeutic agents, to prevent, arrest, abrogate or repair the disease process. Such a model could form the basis for generation and encouragement of clinical trials and also make OCP a model disease to study autoimmunity and design a scientifically based treatment for its eventual cure. The immediate clinical impact of this research will be the generation and availability of highly specific and sensitive serological laboratory test for the early diagnosis of OCP.